hypoglycemia | insulin shock

DIABETES RESEARCH
Hypoglycemia
by Wayne L. Clark

The Juvenile Diabetes Foundation International (JDF) is the largest nongovernment funder of diabetes research in the world. In recent years, it has stepped up its financial commitment to research to enable the rapid transition of new ideas from the laboratory to the daily lives of people living with diabetes. At the same time, it has adopted a philosophy of a quick return for the people who need a cure and borrowed management and accountability practices from the business world.

A JDF Research Task Force reported in late 1997 that there were five priority areas of research that could lead to important advances for people with diabetes, and for those who might develop the disease in the future. In this fourth installment in a series of articles on diabetes research, we take a look at what's happening in one of those areas, minimizing the risk of hypoglycemia while achieving good blood sugar control.

The hallmark of diabetes, and the root cause of most of the damage it does, is too much glucose in the blood. In Type 1 diabetes, the islet cells of the pancreas do not produce insulin, and the only therapy is to replace the insulin. Many people with Type 2 diabetes also need insulin, because the pancreas does not produce enough to meet the body's needs. For these people, that means taking insulin by injection or by infusion through an insulin pump.

Ironically, the very therapy that keeps so many people alive can create the most significant acute complication of diabetes. Hypoglycemia is the opposite of the original problem: not too much glucose in the blood, but too little. Everyone who takes insulin most likely knows the feelings caused by hypoglycemia: sweating, racing heart, shaking, hunger, dizziness, and emotional changes. More than just an inconvenience, if not treated, hypoglycemia can sometimes be deadly.

Hypoglycemia has become a more prevalent problem since the discovery that tight blood sugar control can reduce or eliminate long-term diabetic complications. (Tight control has been defined as keeping blood sugar levels as close to normal as possible with frequent monitoring and, at least for people with Type 1 diabetes, three or more daily injections or an insulin pump.) The Diabetes Complications and Control Trial (DCCT), which involved only people with Type 1 diabetes, and the more recent United Kingdom Prospective Diabetes Study, which enrolled only people with Type 2 diabetes, provided conclusive proof that the lower blood sugar levels are maintained, the lower the incidence of long-term complications. So the trend in diabetes control has emphasized lower blood sugar levels, and the incidence of hypoglycemia has increased.

In fact, the DCCT participants who maintained tight control were three times more likely to experience hypoglycemia. The good news/bad news trade-off is a short-term complication against long-term complications, and the balance is critical.

Another surprising finding of the DCCT was that the conventional wisdom that hypoglycemia is usually caused by not eating enough, taking too much insulin, or getting too much exercise may not be correct. In the study, most episodes of hypoglycemia were independent of those factors, suggesting a fundamental defect in the body's handling of blood glucose regulation in Type 1 diabetes.

In its 1997 Research Task Force report, the Juvenile Diabetes Foundation named hypoglycemia as one of the five most important research focus areas. JDF-funded researchers are working on a number of fronts to solve the mysteries of this seemingly simple but very complex process.

Why Hypoglycemia Occurs
The first step in preventing hypoglycemia is understanding exactly what it is and how it works. With this knowledge, medical researchers may be able to find ways to correct the functional defects that allow hypoglycemia to happen.

This is what we know: People with diabetes have a dysfunctional counterregulatory response to blood sugar levels. In people who do not have diabetes, a decrease in blood sugar levels triggers the release of glucagon from the pancreas. Glucagon is a hormone that causes the liver to convert stored glucose, called glycogen, into glucose and release it into the blood, thus raising the blood sugar level. If that doesn't work, or doesn't work well enough, the adrenal glands release another hormone, epinephrine (also called adrenaline), which causes the liver to convert more glycogen to glucose.

The glucagon response is missing in people with Type 1 diabetes, so the epinephrine response kicks in. (In people with Type 2 diabetes, the glucagon response can be-but isn't always-missing or impaired.) The epinephrine response is a "back-up" system, and it's the source of the sweating and shaking symptoms commonly associated with low blood sugar. When it works, the epinephrine response triggers the release of enough glucose to correct the hypoglycemia or at least bring the blood sugar up long enough for the person to treat it by consuming carbohydrate.

But this response is not the ideal way to control blood sugar levels, and worse, it appears to become less effective over time. It seems that episodes of hypoglycemia somehow create a predisposition for more episodes. It also appears that hypoglycemia lowers the blood sugar level that triggers the counterregulatory response, so that over time, the blood sugar level must fall further before the body responds.

As this threshold lowers, the warning symptoms of hypoglycemia don't appear until the blood sugar level is very low, making it more difficult to treat it in time. This hypoglycemia unawareness is most commonly seen in people with diabetes who have frequent episodes of hypoglycemia, those who have had recent episodes of hypoglycemia, and those who routinely keep their blood sugar levels low to practice tight control.

Hypoglycemia also interferes with blood sugar control because it can be such a frightening experience. People may not attempt tight control for fear of hypoglycemia, and parents of young children especially will often let their children run "high" in order to avoid the feared, middle-of-the-night hypoglycemic episode.

Focusing on the Brain
Researchers have zeroed in on the brain as they look for the primary defect in the counterregulatory system of people with diabetes. The brain is especially sensitive to changes in blood sugar levels, and some researchers think one particular area of the brain, the hypothalamus, may be the key.

Stephanie Amiel, M.D., of King's College in London is using an imaging method called positron emission tomography (PET) to track glucose as it travels through the brain. By labeling glucose with radioactive tracers, she can follow its path throughout the body. She wants to see where in the brain glucose accumulates, where it is metabolized, and how this changes in people with diabetes who are experiencing hypoglycemia. The findings of her JDF-funded research may help determine where and how the brain seemingly "adapts" its ability to take up glucose.

At Yale University School of Medicine, Robert S. Sherwin, M.D., is conducting JDF-funded research into the neurochemistry and function of the brain during hypoglycemia. He and his team will use a microdialysis technique to analyze the fluid between brain cells at various levels of hypoglycemia while the subjects undergo memory testing.

The Yale team will also use an imaging technique called noninvasive nuclear magnetic resonance spectroscopy to investigate what is happening in the brains of people while they are hypoglycemic. The researchers will be able to measure the rate of glucose metabolism and the action of neurotransmitters, the substances that transmit nerve impulses in the brain. A third phase of the project will use another type of imaging study, called functional MRI tests, to measure the effect of hypoglycemia on the changes that occur in various regions of the brain during cognitive tasks such as memorization.

Charles Mobbs, Ph.D., a JDF researcher at Mount Sinai School of Medicine in New York City, is studying the glucose sensitivity of the neurons in the hypothalamus of people with diabetes, with the suspicion that their impaired responsiveness may be due to impaired action of the enzyme glucokinase. If this is the case, it may be possible to develop a drug to restore the glucokinase action to normal.

At the Veteran's Administration Puget Sound Health Care System in Seattle, Dianne Figlewitcz Lattermann, Ph.D., is conducting JDF-funded research into specific nerve cells in the brain that she suspects may be responsible for the decreased response to hypoglycemia. So-called noradrenergic neurons, which help stimulate the brain during stress, may be impaired by hypoglycemia and consequently less able to function normally during subsequent episodes.

In addition, glucose transport across the blood-brain barrier, a mechanism that prevents many substances from leaving the blood and entering the brain-appears to be altered by hypoglycemia. In what may be a primitive protective response, the entrance of glucose into the brain increases during a hypoglycemic episode. If the brain "hoards" glucose this way, it may not recognize the next drop in blood sugar and may not initiate the counterregulatory response.

Stephen Davis, M.D., at Vanderbilt University in Nashville, Tennessee, suspects that the stress hormone cortisol may be at least one factor responsible for "blunting" the counterregulatory response. It is known that exercise can induce hypoglycemia, and also that exercise releases cortisol. Dr. Davis believes that the release of cortisol in response to physiologic stress-whether it be exercise or an episode of hypoglycemia-causes the brain to adapt and inhibit the counterregulatory release of glucagon and epinephrine.

Other Areas of Research
Some researchers believe that the brain is not the only organ responsible for the faulty counterregulatory response. Some suspect the liver. And, at the State University of New York at Stony Brook, Eugenio Cerosimo, M.D., Ph.D., is examining the role of the kidney in the body's defense against hypoglycemia. Normally, the kidney's production of sugar increases when blood glucose levels drop. This reaction may be diminished in people with diabetes.

More than half of hypoglycemic episodes, and the majority of severe episodes, occur at night. Often, people are unaware of these episodes. There is also a strong correlation between low blood sugar at night and increased hypoglycemia during the day. All this has led a number of researchers to consider whether sleep reduces the counterregulatory response.

William V. Tamborlane, M.D., and his colleagues at Yale helped to confirm this theory in their work with adolescents. They found that the counterregulatory response to mild hypoglycemia is reduced during deep sleep. The investigators are now continuing their work to determine why.

It is certain that severe hypoglycemia can sometimes cause coma, permanent brain damage, and even death. Less is known about the effects of less severe or chronic hypoglycemia. Dorothy Becker, M.B., B.Ch., at the Children's Hospital of Pittsburgh believes that it is important to protect children from mild hypoglycemia because it causes a temporary decrease of up to 20% of cognitive capacity. The effect is seen in "mental efficiency" tasks such as memory, attention span, and visual-spatial relationships. Dr. Becker and her colleagues are exploring the use of lactate as a substitute fuel in the absence of glucose as a means of giving children "insurance" against the cognitive deficits of low blood sugar.

Meanwhile, at the University of Western Australia, Timothy Jones, M.B., B.S., is using cognitive testing, electroencephalograms (tracings of brain waves), and MRI scans to measure the brain function of a group of children whose hypoglycemic history is known, to see if and how hypoglycemia has affected them.

Advancing Technology
Achieving tight control while avoiding hypoglycemia requires a balance that is difficult to maintain. Easier and more accurate methods of monitoring blood sugar levels, along with better ways to deliver insulin, could make it easier. There is a great deal of research and development activity focused on devices to do both.

What if you didn't have to draw blood to get a blood sugar level? Some day, this may be possible. Glucose is found not only in blood, but in the fluid between most cells. This interstitial fluid can be found very close to the skin and can be sampled with much less discomfort than is experienced drawing blood with a lancet. Various techniques are being developed to tap and measure the glucose in interstitial fluid, including laser piercing, ultrasound, and microlancets.

For example, the GlucoWatch monitor, which was developed by Cygnus, Inc., leaches glucose through the skin and gives a blood sugar reading every 20 minutes for 12 hours. It has been submitted to the Food and Drug Administration for approval and is expected to be ready for market sometime this year. Michael Pishko, Ph.D., at Texas A&M University is conducting JDF-funded research into the use of ultrasound to extract interstitial fluid, and other researchers are experimenting with skin patches that pull fluid from the skin and can then be "read" in a meter.

Other researchers are looking at various biosensors that react to glucose. Biosensors are compounds that can be implanted in a device, and their reactions can be monitored either visually or by radio signals. Sensors based on glucose oxidase and similar compounds are being tested in a variety of configurations. Joseph Lucisano, Ph.D., and his team at Glysens, Inc., in San Diego have developed one such sensor system and have used it to measure and transmit blood glucose levels in dogs. In ongoing research under a JDF Special Grant, they will attempt to translate this success to human trials.

Homme Hellinga, Ph.D., at Duke University is genetically engineering a protein that reacts to glucose and contains a fluorescent molecule. His JDF project will develop a means to measure the fluorescence and use it to continuously measure blood sugar levels.

On a different tack, Jaime Castano, Ph.D., at Reti Tech, Inc., in El Sobrante, California, is developing tests of visual sensitivity based on the known changes that blood sugar causes in the retina of the eye. Ultimately, these tests could be used for home monitoring.

For many, the ultimate goal of better blood sugar measurement is its application to a "closed loop" system: one that both measures blood glucose levels and administers the appropriate amount of insulin. Already, both pieces of such a system exist; the challenge is to marry them.

The insulin pump manufacturer MiniMed, Inc., has developed the Continuous Glucose Monitoring System, which uses a Teflon catheter that stays under the skin and measures blood glucose levels every five minutes for up to three days. (Currently, the MiniMed system must be prescribed by a doctor.) William V. Tamborlane, M.D., at Yale University Medical School will be conducting a JDF-funded clinical trial this year that will examine how the device may help children and adolescents maintain desired blood sugar levels without the risk of hypoglycemia.

The insulin pump has made blood sugar control more effective and more convenient for many people with diabetes, and if it could respond automatically to blood sugar levels it would become a "virtual pancreas." MiniMed's implantable pump, already approved for use in Europe, combined with the right sensor, could make an implantable closed loop system a reality.

Meanwhile, another company, Animas Corporation, is developing an implantable, optical sensor to measure glucose levels and has developed its own insulin pump.

Hypoglycemia will be conquered only with a better understanding of how it works. Then, using new treatments and prevention strategies, people with diabetes will be able to manage their fear of low blood sugar and have an easier time managing the balance between high and low.

Wayne Clark is a freelance medical and science writer who has written extensively on diabetes. He lives in Maine.

To learn more about the Juvenile Diabetes Foundation, call (800) JDF-CURE (533-2873), or check out their Web site at www.jdf.org.

Reprinted with permission from Diabetes Self-Management
Copyright © 2000 R.A. Rapaport Publishing, Inc.
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